The objective of this proposal is to apply systems biology techniques to the study of signal transduction in cancer progression. The first goal is to develop a novel approach to study signaling in complex systems by identifying global patterns in mRNA, protein expression and posttranslational modifications that report activation of signaling pathways. I will examine activation of the extracellular regulated kinase (ERK) pathway in melanoma progression because melanoma is a well-defined model of cancer progression that involves activation of Raf, MEK (MAPK/ERK kinase), and ERK at early stages. I will then apply this approach to determine whether Rho GTPases are important in melanoma progression, a question that is suggested by preliminary analysis of melanoma cell lines. The second goal of this proposal is to determine the functional significance of ERK and Rho family GTPase signaling in melanoma progression. Specific targets of ERK and Rho family pathways in melanoma progression will be examined to evaluate their contribution to cancer, in an effort to define the mechanisms by which signaling pathways direct cancer progression.